The objective of the proposed research is to understand the interaction of the HIV-1 vpr gene with the host cell. The human immunodeficiency virus (HIV) is a human retrovirus and causes the acquired immune deficiency syndrome (AIDS). Vpr is involved in two important aspects of viral infection and pathogenesis--cell cycle disruption and nuclear transport. Recent experiments indicate Vpr is specifically targeted to the nuclear envelope, and the proposed research tests the hypothesis that this localization is responsible for the role of Vpr in nuclear entry of viral nucleic acids. Three approaches will be used to advance understanding of HIV-1 Vpr function. (1) Viruses carrying mutations in Vpr that disrupt nuclear envelope targeting will be tested for their ability to promote macrophage infection. (2) Nuclear transport factors from the host cell will be tested for biochemical interactions with Vpr, and (3) Vpr-mediated transport will be tested in vitro, discovering functional interactions to elicit the mechanism of Vpr-mediated transport of the viral preintegration complex.